It is disclosed that specific morphinan derivatives having a nitrogen-containing cyclic group or pharmaceutically acceptable acid addition salts thereof, which have a remarkable therapeutic or prophylactic effect against pollakiuria or urinary incontinence, antipruritic effect, analgesic effect, and therapeutic or prophylactic effect against functional bowel disorder, are useful as a therapeutic agent for pollakiuria, antipruritic, analgesic and therapeutic or prophylactic agent for functional bowel disorder (see, e.g., Patent Literatures 1, 2, 3 and 10). However, morphinan derivatives are known to be chemically unstable to light, heat or oxygen (see, e.g., Patent Literature 4), and actually it was confirmed that morphinan derivatives described in Patent Literatures 1 to 3 are also unstable. Therefore, it has been required to develop remedies with a good stability to ensure quality. In addition, the specific morphinan derivatives mentioned above are much slightly soluble in water, and have a problem in the dissolution property particularly in the neutral region. Thus, it has been required to develop remedies with an improved dissolution property in the neutral region as well as a good chemical stability to ensure stable absorption.
As a method for improving the dissolution property of various morphinan derivatives including morphine, a method in which the active ingredient is dissolved in oil or a solubilizer such as polyethylene glycol or surfactant (e.g., Patent Literature 5), and a method in which a remedy is prepared as a composition comprising a nonionic solubilizer, lipophilic antioxidant and aqueous solvent (e.g., Patent Literature 6) have been reported. However, although Patent Literature 5 demonstrates that the active ingredients show a good dissolution property even after 6-month storage, it does not describe the data of chemical stability such as a change in the amount of decomposition products and the like. In Patent Literature 6, although it describes the effect of antioxidants on solubility and stability, the oral administration form is restricted to solutions or gels, and solid formulations such as tablets and capsules are not described. Moreover, the two literatures do not disclose that the dissolution property can be improved by addition of a specific organic acid according to the present invention.
As a method for improving the dissolution property of basic remedies, a method in which acidic compounds such as organic acids are added thereto, a method in which the dissolution rate is increased by pulverizing active substances with a grinder to increase the surface area, or the solid dispersion method in which the active substances are dispersed in a polymer molecule such as polyethylene glycol or polyvinylpyrrolidone is generally used. However, it is known that pulverization not merely increases surface area of particles, but strongly affects on reactivity and stability of the solid, and the problem that destabilization occurs concurrently with improvement of the dissolution property has been pointed out. It has been also reported that, in the solid dispersion method, many amorphous particles of solid dispersions are often generated and that destabilization occurs due to the high surface energy of the amorphous particles (e.g., Patent Literature 1). Thus, it is a very difficult problem to provide a chemically stable preparation with a high dissolution property containing a poorly soluble, unstable compound.
On the other hand, as a method for stabilizing various morphinan derivatives including morphine, a method in which a basic component is added to morphine (e.g., Patent Literature 7), a method in which naloxone is combined with an antioxidant such as sodium thiosulfate or tocopherol (e.g., Patent Literature 8), and a method in which an antioxidant such as sodium thiosulfate or propyl gallate is added to morphinan derivatives to stabilize the preparation (e.g., Patent Literature 4) have been disclosed.
With respect to the effect of addition of organic acids on the chemical stability of morphinan derivatives, stabilized oral preparations comprising naloxone in combination with ascorbic acid and the like (e.g., Patent Literature 8), stabilization by adding an organic acid to naltrexone hydrochloride (e.g., Patent Literature 9), and stabilization by adding ascorbic acid, erythorbic acid or citric acid to morphinan derivatives (e.g., Patent Literature 4) have been reported. However, none of these publications describes the solubility and the stabilizing effect of the organic acids to be added. In fact, it has been reported that stability is decreased when citric acid and tartaric acid are added to morphine (e.g., Patent Literature 7).
Thus, these known techniques do not give the slightest suggestion of adding a specific organic acid to the above-mentioned specific morphinan derivatives having a nitrogen-containing heterocyclic group or a phainiaceutically acceptable acid addition salt thereof in order to provide remedies with an excellent dissolution property and chemical stability.
Non-patent Literature 1: Mitsuru HASHIDA eds., “Designing and Evaluation of Oral Preparations”, 1st Edition, Jihou Co., Ltd., Feb. 10, 1995, p. 167-179
    Patent Literature 1: WO 2004/033457    Patent Literature 2: WO 2005/094826    Patent Literature 3: WO 2006/049248    Patent Literature 4: WO 99/02158    Patent Literature 5: JP 2960169 B    Patent Literature 6: WO 2004/026231    Patent Literature 7: JP 2-160719 A    Patent Literature 8: WO 98/35679    Patent Literature 9: JP 2005-531515 A    Patent Literature 10: WO 2007/055184